Many endogenous and exogenous compounds are observed to have a therapeutic effect in drug development trials in vitro. However, the intended therapeutic effect is often not realised in clinical practice, for example, when compounds are co-administered, because certain compounds induce the expression of the CYP3A4 gene. This induction generates CYP3A4 cytochrome P450 molecules which metabolise compounds before the intended therapeutic effect of each compound can be realised. Accordingly, induction of expression of the CYP3A4 gene interferes with intended dosage, leading to therapeutic failure or sub-optimal treatment.
Induction of CYP3A4 gene expression is a significant problem for drug development because time, resources and expense are wasted in the development of candidate drugs for therapy of particular disease conditions which will ultimately fail or perform sub-optimally in clinical practice.
It would be advantageous to have an animal model for use in drug development trials from which, at an early stage of drug development, one could determine whether a candidate drug would be likely to achieve an intended therapeutic effect in a human.
Such an animal model would not be useful unless at least some of the aspects of the regulation of CYP3A4 gene expression in the human, especially tissue specific expression, are reproduced. This is because in the human, the CYP3A4 gene is expressed in specific tissues, including liver and small intestine, which many compounds inevitably come into contact with when administered for the purpose of therapy. Accordingly, one would be unable to determine whether the bio-availability of a candidate drug would be sufficient for achieving an intended therapeutic effect in clinical practice in a model which does not reproduce the constitutive and xenobiotic induced tissue specific expression of the CYP3A4 gene that is observed in the human.
WO99/61622 and Goodwin et al. 1999 disclose a nucleic acid molecule located 8 kb upstream from the initiation of transcription site of the CYP3A4 gene which regulates transcription of the CYP3A4 gene in response to xenobiotic compounds. These documents do not disclose elements for regulating the constitutive and xenobiotic inducible tissue specific and developmental expression of the CYP3A4 gene observed in a human.
There is a need for an animal model which reproduces at least some aspects of the expression of the CYP3A4 gene in a human, for determining whether a compound, for example, one identified in a drug development trial, would be likely to induce CYP3A4, and hence cause drug-drug interactions, or auto-induction of the metabolism of the drug under study.